Insights into the dynamics of ligand-induced dimerisation via mathematical modelling and analysis

White, Carla; Rottschäfer, Vivi; Bridge, Lloyd

Abstract

The vascular endothelial growth factor (VEGF) receptor (VEGFR) system plays a role in cancer and many other diseases. It is widely accepted that VEGFR receptors dimerise in response to VEGF binding. However, analysis of these mechanisms and their implications for drug development still requires further exploration. In this paper, we present a mathematical model representing the binding of VEGF to VEGFR and the subsequent ligand-induced dimerisation. A key factor in this work is the qualitative and quantitative effect of binding cooperativity, which describes the effect that the binding of a ligand to a receptor has on the binding of that ligand to a second receptor, and the dimerisation of these receptors. We analyse the ordinary differential equation system at equilibrium, giving analytical solutions for the total amount of ligand bound. For time-course dynamics, we use numerical methods to explore possible behaviours under various parameter regimes, while perturbation analysis is used to understand the intricacies of these behaviours. Our simulation results show an excellent fit to experimental data, towards validating the model.

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2021
• Online Publication Date: Jan 24, 2022
• Publication Date: Apr 7, 2022
• Deposit Date: Feb 15, 2022
• Publicly Available Date: Feb 15, 2022
• Journal: Journal of Theoretical Biology
• Print ISSN: 0022-5193
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 538
• Pages: 110996
• DOI: https://doi.org/10.1016/j.jtbi.2021.110996
• Keywords: Applied Mathematics; General Agricultural and Biological Sciences; General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; Modeling and Simulation; General Medicine; Statistics and Probability
• Public URL: https://uwe-repository.worktribe.com/output/9016395
• Additional Information: This article is maintained by: Elsevier; Article Title: Insights into the dynamics of ligand-induced dimerisation via mathematical modelling and analysis; Journal Title: Journal of Theoretical Biology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jtbi.2021.110996; Content Type: article; Copyright: © 2021 The Author(s). Published by Elsevier Ltd.